Various analyte sensors, such as glucose biosensors, have been developed that provide continuous information from the body with regard to analyte concentrations. These sensors thus can be described as operating in vivo, i.e., partially or wholly within a living body. Such in vivo sensors are thus exposed, in varying degree, to the biological environment, and they differ fundamentally in the way in which they are used from ex vivo sensors, such as glucose strip readers, in which a biofluid sample is taken from a subject and conveyed away to an external device for a discrete sample reading. Various methodologies or mechanisms have been applied to the task of transducing the concentration of an analyte of interest into an informative signal (Pearson et al., Analytical Aspects of Biosensors, Ann. Clin. Biochem, 37: 119-145, 2000). Such transducing methodologies include electrochemical methods, such as amperometric, potentiometric, and coulometric methods, by way of example. Other transducing methodologies include optical methods, such as luminescence-, and fluorescence-, and refractive index-based methodologies, by way of example. There are still other methodologies, such as thermal transduction, piezoelectric transduction, and viscosimetric transduction, merely by way of example.
Clinical use of biosensors that provide continuous data has been a significant step toward helping diabetic patients achieve tight control over their blood glucose levels, a goal considered desirable ever since the report of the Diabetes Control and Complications Trial Research Group Study (N. E. J. M. 329: 977-986, 1993). Sensors designed for in vivo operation can be described variously in terms of the particular technologies they employ, the site of their placement in or on a body, and the degree of their invasiveness into the body. Some transcutaneous sensor systems, such as the Freestyle® Navigator™ Continuous Glucose Monitoring System (Abbott Diabetes Care, formerly known as TheraSense, Inc., Alameda, Calif.), are designed for the placement of a sensor portion into a subcutaneous area of the body, while a base portion remains external to the body. The sensor portion includes a membrane that covers its sensing surface, provides a level physical protection of the sensing surface, and also limits the rate of analyte flux to the sensing surface in a way that is advantageous to the electrochemical kinetics of the sensor.
Some transcutaneous continuous sensor systems include a microdialysis loop placed into a subcutaneous area of the body, while a sensor portion remains external to the body. The microdialysis loop provides for the circulation of a solution into and out of the subcutaneous space where it contacts the transducing apparatus of a sensor placed externally, on the skin. The microdialysate fluid emerging from the transit through the subcutaneous space is in equilibrium with the interstitial fluid respect to the concentration of the analyte, and thus is a useful analyte-sensing medium. Examples of microdialysis-based analyte sensing systems suitable for glucose sensing have been described in U.S. Pat. No. 5,640,954 of Pfeiffer et al., filed on May 5, 1995, U.S. Pat. No. 6,091,976 of Pfeiffer et al., filed on Oct. 28, 1998, and U.S. Pat. No. 6,591,126 of Reoper et al., filed on Jul. 20, 2001; U.S. Patent Application Publication No. 2001/0041830 A1 of Varalli et al., filed on May 7, 2001; and European Patent Application No. EP 1153571 A1 of Varalli et al., filed on May 3, 2001.
Still other sensor systems are associated with means or methods that are used to create a disruption, or a wound, or an opening in the skin, or in more functional terms, a cutaneous port out of which fluid exudes. A sensor placed externally, on the skin, is used to sense the analyte concentration in the exuded fluid. This exuded fluid can differ from the interstitial fluid from which it is derived in terms of composition, but with respect to the analyte, is reflective of, or a function of the analyte concentration in the interstitial fluid. The exuded fluid may also differ from its “parent” biofluid according to the process or injury that gave rise to the cutaneous port, which may encompass any of various technologies or methodologies, such as laser burning, ultrasonic disruption, particle propulsion, and reverse iontophoresis, merely by way of example.
An example of an in vivo continuous analyte sensing system that makes use of a cutaneous port is one in which the port is photothermally-induced by a laser technology device as described in U.S. Pat. No. 6,508,785 of Eppstein, issued on Jan. 21, 2003, U.S. Pat. No. 6,530,915 of Eppstein et al., issued on Mar. 11, 2003, U.S. Pat. No. 6,679,841 of Bojan et al., issued on Jan. 20, 2004, and U.S. Pat. No. 6,685,699 of Eppstein et al., issued on Feb. 3, 2004. Further by way of example, another way to create a cutaneous port is through the use of focused ultrasonic waves to disrupt the ordered lipid bilayer of the stratum corneum. This disruption creates pores through which an interstitial fluid-derived wound fluid exudes, whereupon the exuded fluid is used as a sample fluid for a sensor external to the skin. Patents that describe this system include U.S. Pat. No. 6,620,123 of Mitragotri et al., issued on Sep. 16, 2003, U.S. Pat. No. 6,190,315 of Kost et al., issued on Feb. 20, 2001, U.S. Pat. No. 6,234,990 of Rowe et al., issued on May 22, 2001, and U.S. Pat. No. 6,491,657 of Rowe et al., issued on Dec. 10, 2002.
A further example of an approach to continuous in vivo analyte sensing has involves reverse iontophoresis, whereby weak electrical current is applied to a site on the skin to drive compounds outwardly through the skin. Patents describing a reverse iontophoretic sensing system include U.S. Pat. No. 6,023,629 of Tamada, issued on Feb. 8, 2000, U.S. Pat. No. 6,393,318 of Conn et al., issued on May 21, 2002, U.S. Pat. No. 6,438,414 of Conn et al., issued on Aug. 20, 2002, U.S. Pat. No. 5,771,890 of Tamada, issued on Jun. 30, 1998, and U.S. Pat. No. 6,298,254 of Tamada, issued on Oct. 2, 2001. As with other cutaneous port systems, internal from the iontophoretic site or wound surface is interstitial fluid in its native form, with its native immune cell population, albeit disturbed in varying degree by local reaction to the iontophoretic process, and external to the iontophoretic site or wound surface on the skin is an exuded, iontophoretically-driven fluid that comes into contact with the sensing surface.
In vivo or continuous sensing systems have had technical challenges to overcome in order to be able to compare favorably with the high standards of accuracy and dependability established by ex vivo strip-reading glucose sensors. For example, the operation and performance of an in vivo enzyme-based biosensor may be complicated by high rates of analyte flux, such that the relationship between the concentration of glucose in a sample fluid and the response from the biosensor becomes non-linear. This kinetic problem has been solved by the interposition of an analyte-flux-limiting membrane between the sample fluid and the sensing layer of the biosensor, as described in the above-mentioned U.S. Patent Application Publication No. U.S. 2003/0042137A1 of Mao et al. Still other challenges, such as usage limitations, have become evident. For example, data from studies of the recently available, transcutaneous CGMS system of Medtronic MiniMed, indicate spurious, low-glucose-reading incidents, particularly during periods of stillness, such as when a subject is asleep. (See Metzger et al., Reproducibility of Glucose Measurements Using the Glucose Sensor, Diabetes Care, July 2002, Vol. 25, 1185-1191; McGowan et al., Spurious Reporting of Nocturnal Hypoglycemia by CGMS in Patients with Tightly Controlled Type 1 Diabetes, Diabetes Care, September 2002, Vol. 25, 1499-1503; authored by The Diabetic Research in Children Network (DirecNet) Study Group, Accuracy of the Gluco Watch G2 Biographer and the Continuous Glucose Monitoring System During Hypoglycemia, Diabetes Care vol. 27, no. 3, 722-726, March 2004; and Mauras et al., Lack of Accuracy of Continuous Glucose Sensors in Healthy, Nondiabetic Children, Results of the Diabetes Research in Children Network (DirecNet) Accuracy Study, J. Pediatrics 144 (6), 770-775, June 2004.) While nocturnal hypoglycemic events are indeed a clinical reality, especially in patients being aggressively treated with insulin, it has become recognized that false indications of such events are particular fallibilities of the CGMS system that complicate the interpretation of the data obtained using this system. (See Monsod et al., Do Sensor Glucose Levels Accurately Predict Plasma Glucose Concentrations During Hypoglycemia and Hyperinsulinemia?, Diabetes Care, May 2002; and Kaufinan et al., Nocturnal Hypoglycemia Detected with the Continuous Glucose Monitoring System in Pediatric Patients with Type 1 Diabetes, J. Pediatrics 2002; vol. 141, 625-630). Spurious low-glucose-reading incidents are very problematic in the monitoring and treatment of a diabetic subject, as such incidents wrongly indicate that a euglycemic subject is hypoglycemic. As an example, when a spurious, low-glucose reading is used as a signal to control insulin dosage, a subject may receive an improper or a reduced dose of insulin and thus be put at risk for becoming hyperglycemic. Spurious low glucose readings can be further problematic as they may lead to incorrectly calibrated sensors, resulting in subsequent false, high glucose readings, which may reduce the credibility and usefulness of the alarm function, by way of example. Further development of biosensor components and biosensors for continuous in vivo monitoring of analyte levels, such as glucose levels, is desirable.